In silico Strategies to Probe Stereoselective Interactions of Multidrug Resistant Transporter P-glycoprotein

ATP-dependent xenobiotic efflux transporter P-glycoprotein (P-gp) limits the cellular accumulation of many therapeutically important drug molecules. The most prominent of these are CNS active compounds and the potential chemotherapeutic agents. Co-administration of chemotherapeutic agents with modulators of P-glycoprotein has been advocated as a promising concept to circumvent drug resistance in tumor cells. Several pharmacoinformatics strategies to investigate ligand-P-glycoprotein interactions profiles revealed that these are promiscuous, multi-site and conformational dependent processes that take place in asymmetric 3D space within the binding cavity of P-gp. Therefore, avoiding stereo-selectivity associated with ligand-protein interaction may compromise efficiency of the QSAR and other modeling strategies. Within this article, several SAR and QSAR strategies in combination with molecular docking studies on stereoisomeric inhibitors of P-gp will be highlighted to further explore the stereoselectivity of ligand-P-glycoprotein interaction.